PROJECT SUMMARY Asthma is one of the most common chronic diseases in the United States and is an important cause of morbidity and mortality, not only in the US, but also worldwide. Over the past decade, obesity has been recognized as an important risk factor for asthma. Epidemiologic studies reveal associations of obesity with the development of asthma, increased risk of asthma exacerbations, and greater risk of hospitalization for asthma. Several studies indicate that conventional asthma therapy has reduced efficacy in obese people with asthma. Our novel preliminary data reveals that signaling through the glucagon-like peptide-1 receptor (GLP- 1R) significantly inhibited lung IL-5 and IL-13 protein and airway eosinophilia in murine in vivo models of both: a) the early innate response prior to the onset of robust adaptive immunity, and b) adaptive immune responses driven by CD4+ Th2 cells. These preliminary data lead us to propose the hypothesis that GLP-1R signaling is a negative regulator of both the early innate and adaptive immune responses in a model of asthma generated by Alternaria airway challenge during high fat diet-induced obesity. This proposal will determine how GLP-1R signaling regulates the activation of host innate immune cells and signaling pathways to the microbial antigens in Alternaria alternata that lead to allergic inflammatory responses in obesity. The proposed studies are paradigm shifting in that they will determine the mechanisms by which GLP-1R signaling: a) inhibits allergen-induced group 2 innate lymphoid cell (ILC2) function and airway epithelial cell IL- 33 production, and b) modulates dendritic cell migration and activation of naive T cells, and T regulatory cell (Treg) function. These proposed studies are clinically relevant in that we will define potential mechanisms by which a GLP-1R agonist, currently FDA approved for the treatment of obesity and diabetes, may be effective in the treatment of allergic airway inflammatory diseases such as asthma in the setting of obesity. The proposed studies will advance the field by defining a novel mechanism that negatively regulates immune responses to the protease containing allergens such as Alternaria alternata in the setting of obesity.